Recently we made the surprising observations that a subpopulation of Mycobacterium tuberculosis (M. tb)-expanded human CD4+CD25+FoxP3+ cells produce Rho GDP dissociation inhibitor (D4GDI), which inhibits M. tb growth in monocyte-derived macrophages (MDMs). Based on our data, we hypothesize that defective D4GDI production by a subpopulation of CD4+CD25+FoxP3+ cells and enhanced production of IL-10 and TGF- by CD4+CD25+FoxP3+ cells in HIV-infected persons with LTBI contribute to enhanced M. tb growth in their macrophages and increasing the risk for progression to active TB. In aim 1 we will test this hypothesis by comparing the number of FOXP3+D4GDI+ cells and their effect on virulent M. tb growth in MDMs of HIV-LTBI+ and HIV+LTBI+ persons. We will also use siRNA to D4GDI and recombinant D4GDI to determine the role of FOXP3+D4GDI+ cells in the progression to active TB. In aim 2 we will characterize the phenotype and function of D4GDI-producing FoxP3+ cells in HIV-LTBI+ and HIV+LTBI+ persons and HIV+TB patients with low CD4 count (<100) and with high CD4 count (>100). These studies will improve our understanding of the mechanisms that mediate susceptibility to TB in HIV+ persons, and facilitate development of interventions to improve Foxp3+D4GDI+ cell function and prevent progression of LTBI in HIV-infected persons.